Novel tumor markers in the serum of testicular germ cell cancer patients: a review

Current Biomarker Findings Dovepress open access to scientific and medical research Review Open Access Full Text Article Current Biomarker Findings downloaded from https://www.dovepress.com/ by 37.59.46.207 on 12-Jul-2018 For personal use only. Novel tumor markers in the serum of testicular germ cell cancer patients: a review This article was published in the following Dove Press journal: Current Biomarker Findings 9 September 2014 Number of times this article has been viewed Isabella Syring Stefan C Müller Jörg Ellinger Department for Urology and Pediatric Urology, University Hospital Bonn, Bonn, Germany Abstract: Serum tumor markers have an important role in the management of patients with testicular cancer. They are useful for diagnosis, staging and risk assessment, follow-up, evaluation of response, and early detection of relapse. Alpha-fetoprotein, human chorionic gonadotropin, and lactate dehydrogenase are established serum markers in testicular cancer, but they have a limited sensitivity. Ongoing research may lead to the identification of novel biomarkers. Therefore, we review the experimental analyses for nucleic acids, circulating tumor cells, and proteins as potential biomarkers in the serum of testicular germ cell cancer patients. Keywords: biomarker, serum, testicular germ cell cancer Introduction Testicular germ cell cancer (TGCT) is the most common malignant tumor in men aged 15–44 years, with its incidence rising in many countries; however, mortality rates remain low and many men are cured.1 The main factors contributing to the excellent cure rates are careful staging at the time of diagnosis, adequate early treatment based on polychemotherapy, radiotherapy, and surgery, as well as strict follow-up and salvage therapies. The introduction of the highly specific serum tumor markers alphafetoprotein (AFP) and human chorionic gonadotropin (HCG) especially improved the clinical management of patients with TGCT, and these markers nowadays play important roles in diagnosis, risk stratification, treatment monitoring, and surveillance.2 However, about 50% of TGCT patients have normally ranged tumor markers;3 thus, additional markers could be helpful for the clinician. Several researchers are working on improved noninvasive biomarkers. We will discuss recent advances in the field of circulating tumor cells (CTCs), cell-free nucleic acids, and proteins. Nucleic acids microRNA Correspondence: Isabella Syring Universitätsklinikum Bonn, Klinik und Poliklinik für Urologie und Kinderurologie, Sigmund-FreudStraße 25, 53105 Bonn, Germany Tel +49 228 287 15109 Fax +49 228 287 14185 Email 133 submit your manuscript | www.dovepress.com Current Biomarker Findings 2014:4 133–137 Dovepress © 2014 Syring et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php http://dx.doi.org/10.2147/CBF.S66068 Powered by TCPDF (www.tcpdf.org) microRNAs (miRNAs) are small RNA molecules involved in several essential biological processes4 that cover embryogenic development, cell differentiation, apoptosis, and tumorigenesis.5 miRNAs have the potential to qualify as biomarkers in various malignancies because they mostly reveal a high stability in body fluids.5,6 Palmer et al7 recently demonstrated that miR-371-373 and miR-302 clusters are highly overexpressed in all malignant germ cell tumors (compared to normal control tissues and benign tumors), irrespective of patient age, histologic subtype, or anatomic site of the tumor.4 High expression of the miR-371-3 and miR-302 clusters Dovepress Current Biomarker Findings downloaded from https://www.dovepress.com/ by 37.59.46.207 on 12-Jul-2018 For personal use only. Syring et al was demonstrated in the serum of a 4-year-old boy with a yolk sac tumor and miRNA levels declined after chemotherapy.4 This finding stimulated research enormously, and Belge et al confirmed high levels of serum miR-371-3 with a standardized quantitative real-time polymerase chain reaction technique in a small cohort (n=11) of TGCT patients;6 unfortunately, HCG/AFP levels were not indicated in the report. Serum levels of each of the three miRNAs (miR371, miR-372, and miR-373) decreased significantly after treatment.6 Dieckmann et al confirmed these results in a subsequent study and, most importantly, showed that the diagnostic information of the novel markers was superior to the classical tumor markers AFP and HCG (increased in four and two out of 24 TGCT patients, respectively).5 Patients in clinical stage I also showed a decline of circulating miRNAs following orchidectomy. Further research in a series with 80 TGCT patients confirmed the excellent sensitivity of serum miRNAs:8 an increase of miR-371, miR-372, miR-373, or miR-367 was observed in 98% of the examined TGCT patients; the miRNAs thus outperformed AFP (36%) and HCG (57%). Our own data also confirm the improved sensitivity (85%) and specificity (99%) of miR-371 when compared to AFP (14%) and HCG (37%).9 In summary, several independent studies indicate an increase of miR-371–373 in TGCT patients irrespective of their histological subtypes and, therefore, result in a better diagnostic performance than AFP/HCG. DNA DNA fragments also circulate in a patient’s blood, and its quantification seems to be a universal cancer biomarker.10 Earlier, we demonstrated an increase of short, presumably apoptotic DNA fragments in a cohort of 74 patients with TGCT (compared to 35 control subjects).11 The increase of genomic DNA allowed us to identify TGCT patients with a sensitivity of 84% and a specificity of 97%.11 Whereas mitochondrial DNA is also released into circulation, the underlying mechanism seems to be different from genomic DNA: the quantification of mitochondrial DNA was less sensitive (60%) at a similar specificity (94%) in the same study cohort.12 Notably, the diagnostic performance of genomic and mitochondrial DNA was superior to that of AFP and HCG (24% and 43% sensitivity, respectively), and cell-free serum DNA levels were similar in seminoma and non-seminoma TGCT. The analysis of circulating DNA allows for the detection of tumor-specific alterations. DNA hypermethylation is frequent during carcinogenesis, and also occurs in TGCT. Serum DNA 134 Powered by TCPDF (www.tcpdf.org) submit your manuscript | www.dovepress.com Dovepress hypermethylation in the above mentioned cohorts was detected more frequently in patients with TGCT than in healthy individuals, including APC (...truncated)